Small non-coding RNA molecules (microRNAs, miRNAs) regulate genes involved in brain functions negatively affected in neuropsychiatric disorders. We propose to test the hypothesis that exosomes, secretory vesicles recently shown to comprise miRNAs, harbor differential miRNA content in the postmortem brain tissue of patients diagnosed with either bipolar disorder (BD) or schizophrenia (SCH), or of normal controls. In addition, we will identify major cell-category (neurons, glia) - and brain region- specific miRNA profile in BD. The results of this analysis may help elucidate neuropathological mechanisms underlying BD and SCH as well as identify biological markers for BD and SCH. Important characteristic of exosomes is that, once secreted, they are able to attach themselves to recipient cells, release their content including regulatory miRNAs, and thus potentially modulate the functioning of the recipient cell. miRNAs are known to regulate the expression of human genes involved in cell processes and functions negatively affected in neuropsychiatric disorders, such as synaptic development and maturation, learning and memory. Our preliminary data indicate that exosomes isolated from frozen postmortem brain tissue contain well preserved miRNAs. To test the hypothesis that exosomal miRNA content reflects neuropsychiatric disease specific-aberrations, Specific Aim 1 will compare exosomal miRNA contents in the frozen postmortem prefrontal cortices (PFC, Brodmann area, BA, 9) from the patients diagnosed with SCH, BD and matching controls from McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center) and from BrainNet Europe II (BNE, a consortium of 18 brain banks across Europe). Specific Aim 2 of this proposal is to establish cell-type specific miRNA profile via laser capture microscopy (LCM) mapping of neurons and glia in brain regions participating in mood manifestations (BA9, BA24 and ventral striatum) in BD and control samples. This Aim will test the hypothesis that major cell- categories in different but interacting brain regions display specifically altered miRNA profiles in BD in comparison to controls. The experiments described in this proposal apply an innovative approach towards the search for biological markers for bipolar disorder (BD) and schizophrenia (SCH). The broad significance of the study is twofold: 1) provide the ground work for the development of tools needed to identify and monitor the population at risk;2) generate information necessary for formulating new and/or testing current explanations of the causes of BD and SCH. PUBLIC HEALTH RELEVANCE: Small non-coding RNA molecules (microRNAs, miRNAs) are known to regulate genes involved in brain functions negatively affected in neuropsychiatric disorders. This proposal is aims to: 1) examine whether exosomes, secretory vesicles recently shown to contain miRNAs, harbor differential miRNA content in the postmortem brain tissue of patients diagnosed with either bipolar disorder (BD) or schizophrenia (SCH), or of normal controls;and 2) determine major cell-category- and brain region- specific miRNA profiles in BD. The results of this analysis may help elucidate neuropathological mechanisms underlying BD and SCH as well as identify biological markers for BD and SCH.